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Note

The following guide was issued by the FDA for its inspectors in an effort to benchmark the various FDA requirements of water systems for the inspection process. By establishing this consensus of evaluation for inspection criteria the inspection process and its results should therefore be consistent from project to project. You will find that the drawings presented in this guide are of poor quality. They will however be replace by drawings of better quality.

We have provided this Guideline as a design/engineering tool. By reviewing this Guideline the engineer or designer will better understand and learn what to expect from an FDA audit and inspection. By knowing and anticipating what to expect from an FDA audit you can better incorporate those points into your design,  making the entire process a little complicated.

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GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS

July, 1993
The Division of Field Investigations
Office of Regional Operations
Office of Regulatory Affairs
U.S. Food & Drug Administration

This guide discusses, primarily from a microbiological aspect, the review and evaluation of high purity water systems that are used for the manufacture of drug products and drug substances. It also includes a review of the design of the various types of systems and some of the problems that have been associated with these systems.

As with other guides, it is not all-inclusive, but provides background and guidance for the review and evaluation of high purity water systems. The Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories (May, 1993) provides additional guidance.

TABLE OF CONTENTS

I SYSTEM DESIGN
II SYSTEM VALIDATION
III MICROBIAL LIMITS
IV WATER FOR INJECTION SYSTEMS
V STILL
VI HEAT EXCHANGERS
VII HOLDING TANK
VIII PUMPS
IX PIPING
X REVERSE OSMOSIS
XI PURIFIED WATER SYSTEMS
XII PROCESS WATER
XIII INSPECTION STRATEGY

I - SYSTEM DESIGN

One of the basic considerations in the design of a system is the type of product that is to be manufactured. For parenteral products where there is a concern for pyrogens, it is expected that Water for Injection will be used. This applies to the formulation of products, as well as to the final washing of components and equipment used in their manufacture. Distillation and Reverse Osmosis (RO) filtration are the only acceptable methods listed in the USP for producing Water for Injection. However, in the bulk Pharmaceutical and Biotechnology industries and some foreign companies, Ultra Filtration (UF) is employed to minimize endotoxins in those drug substances that are administered parenterally.

For some ophthalmic products, such as the ophthalmic irrigating solution, and some inhalation products, such as Sterile Water for Inhalation, where there are pyrogen specifications, it is expected that Water for Injection be used in their formulation. However, for most inhalation and ophthalmic products, purified water is used in their formulation. This also applies to topicals, cosmetics and oral products.

Another design consideration is the temperature of the system. It is recognize that hot (65 to 80C) systems are self-sanitizing. While the cost of other systems may be less expensive for a company, the cost of maintenance, testing and potential problems may be greater than the cost of energy saved.

Whether a system is circulating or one-way is also an important design consideration. Obviously, water in constant motion is less liable to have high levels of contaminants. A one-way system is basically a "dead-leg".

Finally, and possibly the most important consideration, is the risk assessment or level of quality that is desired. It should be recognize that different products require different quality waters. Parenterals require very pure water with no endotoxins. Even with topical and oral products there are factors that dictate different qualities for water. For example, preservatives in antacids are marginally effective, so more stringent microbial limits have to be set. The quality control department should assess each product manufactured with the water from their system and determine the microbial action limits based on the most microbial sensitive product. In lieu of stringent water action limits in the system the manufacturer can add a microbial reduction step in the manufacturing process for the sensitive drug product(s).

II - SYSTEM VALIDATION

A basic reference used for the validation of high purity water systems is the Parenteral Drug Association Technical Report N4 titled "Design Concepts for the Validation of Water for Injection Systems."

The introduction provides guidance and states that; "validation often involves the use of an appropriate challenge. In this situation, it would be undesirable to introduce micro-organisms into an on-line system; therefore, reliance is placed on periodic testing for microbiological quality and on the installation of monitoring equipment at specific checkpoints to ensure that the total system is operating properly and continuously fulfilling its intended functions."

In the review of a validation report, or in the validation of a high purity water system, there are several aspects that should be considered. Documentation should include a description of the system along with a print. The drawing needs to show all equipment in the system from the water feed to points of use. It should also show all sampling points and their designations. If a system has no print, it is usually considered an objectionable condition. The thinking is if there is no print,   then how can the system be validated? How can the quality control manager or microbiologist know where to sample? In those facilities observed without updated prints, serious problems were identified in these systems. The print should be compared to the actual system annually to insure its accuracy, to detect unreported changes and confirm reported changes to the system.

After all the equipment and piping has been verified as installed correctly and working as specified, the initial phase of water system validation can begin. During this phase the operational parameters and the cleaning/sanitation procedures and frequencies will be developed. Sampling should be daily after each step in the purification process and at each point of use for two to four weeks. The sampling procedure for point of use sampling should reflect how the water is to be drawn e.g. if a hose is usually attached the sample should be taken at the end of the hose. If the SOP calls for the line to be flushed before use of the water from that point, the sample is taken after the flush. At the end of the two to four week time period the firm should have developed its SOP's for operation of the water system.

The second phase of the system validation is to demonstrate that the system will consistently produce the desired water quality when operated in accordance with the SOP's. The sampling is performed as in the initial phase and for the same time period. At the end of this phase, the data should demonstrate that the system will consistently produce the desired quality of water.

The third phase of validation is designed to demonstrate that when the water system is operated in accordance with the SOP's over a long period of time it will consistently produce water of the desired quality. Any variations in the quality of the feedwater will be picked up during this phase of validation. Sampling is performed according to routine procedures and frequencies. For water for injection systems the samples should be taken daily from a minimum of one point of use, with all points of use tested weekly. The validation of the water system is completed when the firm has a full year worth of data.

While the above validation scheme is not the only way a system can be validated, it contains the necessary elements for validation of a water system. First, there must be data to support the SOP's. Second, there must be data demonstrating that the SOP's are valid and that the system is capable of consistently producing water that meets the desired specifications. Finally, there must be data to demonstrate that seasonal variations in the feedwater does not adversely affect the operation of the system of the water quality.

The last part of the validation is the compilation of the data, with any conclusions into the final report. The final validation report must be signed by the appropriate people responsible for the operation and quality assurance of the water system.

A typical problem that occurs is the failure of operating procedures to preclude contamination of the system with non-sterile air remaining in a pipe after drainage. In a system, as illustrated in Figure 1, a typical problem occurs when a washer or hose connection is flushed and then drained at the end of the operation. After draining, this valve (the second of the system) is closed. If on the next day or start-up of the operation the primary valve off of the circulating system is opened, then the non-sterile air remaining in the pipe after drainage would contaminate the system. The solution is to provide for operational procedures that provide for opening the secondary valve before the primary valve to flush the pipe prior to use.

Another major consideration in the validation of high purity water systems is the acceptance criteria. Consistent results throughout the system over a period of time constitute the primary element.

III - MICROBIAL LIMITS

Water For Injection Systems

Regarding microbiological results, for Water for Injection, it is expected that they be essentially sterile. Since sampling frequently is performed in non-sterile areas and is not truly aseptic, occasional low level counts due to sampling errors may occur. Agency policy, is that less than 10 CFU/100ml is an acceptable action limit. None of the limits for water are pass/fail limits. All limits are action limits. When action limits are exceeded the firm must investigate the cause of the problem, take action to correct the problem and assess the impact of the microbial contamination of products manufactured with the water and document the results of their investigation.

With regard to sample size, 100 - 300 ml is preferred when sampling Water for Injection systems. Sample volumes less than 100 ml are unacceptable.

The real concern in WFI is endotoxins. Because WFI can pass the Lower Action Limit (LAL) endotoxin test and still fail the above microbial action limit, it is important to monitor WFI systems for both endotoxins and micro-organisms.

Purified Water Systems

For purified Water Systems, microbiological specifications are not as clear. US Pharmacopeia, USP XXII specifications, as it complies with Federal Environmental Protection Agency regulations for drinking water, are recognized as being minimal specifications. There have been attempts by some to establish meaningful microbiological specifications for purified water. The CFTA proposed a specification of not more than 500 organisms per ml. The USP XXXII has an action guideline of not greater than 100 organisms per ml. Although microbiological specifications have been discussed, none (other than EPA Standards) have been established. Agency policy is that any action limit over 100 CFU/ml for a purified water system is unacceptable.

The purpose of establishing any action limit or level is to assure that the water system is under control. Any action limit established will depend upon the overall purified water system and further processing of the finished product and its use. For example, purified water used to manufacture drug products by cold processing should be free of objectionable organisms. We have defined "objectionable organisms" as any organisms that can cause infections when the drug product is used as directed or any organism capable of growth in the drug product. As pointed out in the Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories, the specific contaminant, rather than the number is generally more significant.

As represented in Figure 2, organisms exist in a water system either as free floating in the water or attached to the walls of the pipes and tanks. When they are attached to the walls they are known as biofilm, which continuously sough off organisms. Thus, contamination is not uniformly distributed in a system and the sample may not be representative of the type and level of contamination. A count of 10 CFU/ml in one sample and 100 or even 1000 CFU/ml in a subsequent sample would not be unrealistic.

Thus, is establishing the level of contamination allowed in a high purity water system used in the manufacture of a non-sterile product requires an understanding of the use of the product, the formulation (preservative system) and manufacturing process. For example, antacids, which do not have an effective preservative system, require an action limit below the 100 CFU/ml maximum.

The USP gives some guidance in their monograph or microbiological Attributes of Non-sterile Products. It points out that, "The significance of micro-organisms in non-sterile pharmaceutical products should be evaluated in terms of the use of the product, the nature of the product, and the potential harm to the user." Thus, not just the indicator organisms listed in some of the specific monographs present problems. It is up to each manufacturer to evaluate their product, the way it is manufactured, and establish an acceptable action level of contamination, not to exceed the maximum, for the water system, based on the highest risk product manufactured with the water.

IV - WATER FOR INJECTION SYSTEMS

In the review and evaluation of Water for Injection Systems, there are several concerns.

Pre-treatment of feedwater is recommended by most manufacturers of distillation equipment and is definitely required for RO units. The incoming feedwater quality may fluctuate during the life of the system depending upon several seasonal variations and other external factors beyond the control of the pharmaceutical facility. For example, in the spring (at least in the N.E.), increases in gram negative organisms have been known. Also, new construction or fires can cause a depletion of water stores in old mains which can cause an influx of heavily contaminated water of a different flora.

A water system should be designed to operate within these anticipated extremes. Obviously, the only way to know the extremes is to periodically monitor feedwater. If the feedwater is from a municipal water system, reports from the municipality testing can be used in lieu of in-house testing.

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